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Mini et al. Cancer Drug Resist 2020;3:225-31 I http://dx.doi.org/10.20517/cdr.20220.10 Page 229

mainly due to restoration of homologous recombination, replication fork dynamics, PARylation balance,
loss of PARP1, and drug efflux, the study of biomarkers predictive of this phenomenon is pivotal, as is the
identification of their most active schedule (e.g., monotherapy vs. combination therapy) or sequence of
treatment.

As mentioned above, the occurrence of intrinsic or acquired drug resistance represents a major reason for
[24]
anticancer treatment failure. Kumar et al. discussed traditional and more recently emerged mechanisms
of tumor drug resistance, thus providing an overview of this complex phenomenon. In addition to classical
mechanisms represented mainly by efflux pumps or detoxifying enzymes, other key processes involved
in drug resistance (e.g., tumor heterogeneity, reactivation of drug targets, hyperactivation of alternative
pathways, cross-talk with the microenvironment, altered DNA response and DNA repair, epigenetic
alterations, impairment in apoptosis/autophagy, and presence of cancer stem cells) have been widely
investigated in recent years. Examples are represented by the inactivation of transcription factors such
as Forkhead box proteins by the hyperactivation of PI3K/Akt signaling and the protective role of focal
adhesion kinase (FAK alias PTK2) through induction of NF-κB pathway mediated cytokine production
in response to DNA damage. Due to the complexity of tumor drug resistance, the concurrent targeting of
multiple mechanisms responsible for this phenomenon could represent the optimal strategy.

Concerning the development of tumor drug resistance, intratumoral heterogeneity represents a critical
factor. Breast cancer, the most frequent neoplasms worldwide, is a highly heterogenous disease from the
[25]
molecular point of view and this directly impacts response to drug treatment. Belizario and Loggulo
reviewed the state-of-the-art of the current knowledge on breast cancer molecular subtypes and their
relationships with prognosis and treatment response. In addition to the already acquired findings, the
current availability of the newest biomolecular technologies combined with computational integrative
methods will obtain an increasingly accurate prediction of treatment response by interrogating specific
pivotal areas such as tumor and peritumoral microenvironments and by identifying new biomarkers useful
to further stratify patients and ameliorate personalized treatment.

Similar considerations may be applied to the heterogeneity of GIST, a rare but highly lethal cancer. After
the identification of gain-of-function mutations in KIT and PDGFRA receptor genes that opened the way
to the treatment with inhibitors of c-KIT and platelet-derived growth factor receptor A (PDGFRA) tyrosine
kinase receptors (e.g., imatinib and newer analogs) in succinate dehydrogenase (SDH) competent GIST,
it is today known that mutations in other molecules, such as BRAF or RAS, or mutations in SDH subunits
that lead to SDH deficient GISTs represent different subtypes with specific features affecting prognosis
[26]
and clinical outcome. The review of Ravegnini et al. focuses on tumor alterations in GISTs in relation
to response to the available drugs. A mention of GIST germline DNA alterations and their possible role in
drug efficacy/resistance is also provided, although this matter is still the subject of debate.

Liver cancers are substantially unresponsive to cytotoxic anticancer agents. Targeted drugs, in particular
antiangiogenic drugs, are today approved for the treatment of hepatocellular carcinoma, in which, however,
[27]
they are endowed with low efficacy. Alonso-Peña et al. reviewed molecular alterations (mainly, germline
polymorphisms and somatic mutations) that have been suggested to confer drug resistance to liver cancers
(i.e., hepatocellular carcinoma and cholangiocarcinoma). However, despite the availability of a relevant
number of studies that report potential associations among polymorphisms/mutations in genes codifying
transporters or detoxifying enzymes, changes in molecular targets, enhanced DNA repair mechanisms,
altered balance between survival and apoptosis pathways, tumor microenvironment and epithelial-
mesenchymal transition, and cytotoxic or targeted anticancer drug efficacy and/or toxicity, no solid data
are currently available and further investigation is needed.